Research in recent years shows that PI3K-AKT-mTOR signalling pathways play a key role in the growth, proliferation, invasion and metastasis of tumor cells, and blocking of PI3K-AKT-mTOR signalling pathways in the cells can inhibit the proliferation of tumor cells, and even promote apoptosis of tumor cells. In various kinds of human tumors, some key proteins in PI3K-AKT-mTOR signalling pathways may be overly activated, due to mutation or amplification of encoding genes, for example, the mutation or amplification of the upstream receptor tyrosine kinase, the mutation or amplification of PIK3CA gene encoding p110α catalytic subunit in various tumor cells, over activation of Akt and PDK1, and general deletion in the negative regulator PTEN.
Mammalian target of rapamycin, mTOR, which is one of the most important substrates for Akt, is a non-classical serine/threonine protein kinase of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. mTOR signalling pathway can regulate a large number of life processes by integrating the signals transmitting from nutrition molecules, the energy status and growth factors, and thus is a key pathway for regulating the growth and proliferation of cells. Abnormal activation of mTOR signalling pathways is a common character of occurrence and development of various tumors, thus it becomes a hot spot in the research and development of an antitumor inhibitor.
However, it has been found that there are at least two functional complexes, i.e., mTORC1 and mTORC2, which mediate both related and independent biological signaling. Clinically used Rapamycin drug, including Rapamycin and analogues thereof, binds to FKBP12-rapamycin binding domain (FRB) around mTORC1 catalytic site via allostery, to exert the effects of partial inhibition of mTOR protein. These compounds neither directly inhibit mTORC2, nor completely block all the signals mediated by mTORC1. Although the rapamycin drug has shown cercern clinical efficacy in some tumor spectra, but the action mode of such kind of drug can not reach full potential of the mTOR targeted anticancer drugs. Especially, in some major solid tumors, AKT hyperphosphorylation (activation) mediated by mTORC2 is vital for maintenance and development of the tumors, but mTORC2 can not be inhibited by Rapamycin drugs.
The development of ATP-competitive and specific small molecule inhibitors of mTOR provides the possibility for treating a variety of cancers. Compared with Rapamycin drugs, some ATP-competitive inhibitors reported recently have shown better inhibitory effect on the growth and survival, protein synthesis, biological energy metabolism of tumor cells. In animal studies, this kind of drug has a strong single-drug antitumor activity on MDA361 breast cancer, U87MG glioma, A549 and H1975 lung cancer, A498 and 786-O kidney cancer.
In summary, as mTOR signaling pathway is involved in a variety of tumor spectra, the development of a more effective mTOR inhibitor provides fresh thinking and a new strategy for a novel broad-spectrum anti-tumor drug. Recently, several mTOR inhibitors have been entered into the clinical research phase, which indicates that the ATP-competitive inhibitor of mTOR may be a new generation of anticancer drug to be used in clinic.
The present inventor has confirmed that the mTOR inhibitor is an ATP-competitive inhibitor, thus its mechanism of action is different from that of Rapamycin drugs. In addition, the present inventors obtained a class of novel pyridopyrimidine or pyrimidopyrimidine compounds by rational design and comprehensive consideration of the factors such as water solubility, metabolic stability and the like of the compounds, based on previously reported compounds. Such compounds show good mTOR inhibition activity at the encymic and cellular levels. After further optimization and screening, these compounds are expected to become readily prepared anticancer drugs with higher activity.